Throughout this application various publications are referenced to by arabic numerals within parenthesis. Full bibliographic citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures for these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Mouse peritoneal macrophages and cells of the J774 macrophage-like cell line express organic transporters that remove Lucifer Yellow and other water soluble anionic dyes from the cells' cytoplasmic matrix. (1) Lucifer Yellow is transported from the cytoplasmic matrix into endosomes, delivered from endosome to lysosomes, and also secreted into the extracellular medium. (1,2) Within 30 minutes after the dye is introduced into the cytosol by ATP-mediated permeabilization of the plasma membrane, 80-85% of the dye is secreted by the cells into the medium; the dye remaining in the cells is present within the endocytic compartment and ultimately is transferred to lysosomes. Probenecid and sulfinpyrazone inhibit both intracellular sequestration and secretion of Lucifer Yellow. Although the endogenous substrates for these organic anion transporters are not known, many metabolites and secreted mediators, including bilirubin, glutathione, prostaglandins, and leukotrienes, are substrates for organic anion transporters in various polarized epithelia.
Many antibiotics are organic anions; indeed, probenecid was developed specifically to inhibit the secretion of penicillin G by organic anion transporters of the renal tubular epithelium.